Thank you for visiting nature.com. You are using a browser version with
limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off
compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site
without styles and JavaScript.

Subjects

Abstract

Leptin, a hormone produced in white adipose tissue, acts in the brain to communicate fuel status, suppress appetite following a meal, promote energy expenditure and maintain blood glucose stability1,2. Dysregulation of leptin or its receptors (LEPR) results in severe obesity and diabetes3,4,5. Although intensive studies on leptin have transformed obesity and diabetes research2,6, clinical applications of the molecule are still limited7, at least in part owing to the complexity and our incomplete understanding of the underlying neural circuits. The hypothalamic neurons that express agouti-related peptide (AGRP) and pro-opiomelanocortin (POMC) have been hypothesized to be the main first-order, leptin-responsive neurons. Selective deletion of LEPR in these neurons with the Cre–loxP system, however, has previously failed to recapitulate, or only marginally recapitulated, the obesity and diabetes that are seen in LEPR-deficient Leprdb/db mice, suggesting that AGRP or POMC neurons are not directly required for the effects of leptin in vivo8,9,10. The primary neural targets of leptin are therefore still unclear. Here we conduct a systematic, unbiased survey of leptin-responsive neurons in streptozotocin-induced diabetic mice and exploit CRISPR–Cas9-mediated genetic ablation of LEPR in vivo. Unexpectedly, we find that AGRP neurons but not POMC neurons are required for the primary action of leptin to regulate both energy balance and glucose homeostasis. Leptin deficiency disinhibits AGRP neurons, and chemogenetic inhibition of these neurons reverses both diabetic hyperphagia and hyperglycaemia. In sharp contrast to previous studies, we show that CRISPR-mediated deletion of LEPR in AGRP neurons causes severe obesity and diabetes, faithfully replicating the phenotype of Leprdb/db mice. We also uncover divergent mechanisms of acute and chronic inhibition of AGRP neurons by leptin (presynaptic potentiation of GABA (γ-aminobutyric acid) neurotransmission and postsynaptic activation of ATP-sensitive potassium channels, respectively). Our findings identify the underlying basis of the neurobiological effects of leptin and associated metabolic disorders.

Search for Cheng-Hao Chien in:

Search for Peng Wang in:

Search for Dong Kong in:

Contributions

J.X., C.L.B. and D.K. designed the experiments, analysed data and wrote the manuscript. J.X. and C.L.B. performed the experiments with the help of C.S.L., X.Y., C.-H.C. and P.W. J.X. constructed AAV vectors. J.X. and C.-H.C. performed electrophysiology. C.L.B. and C.S.L. performed STZ-related studies. J.X., C.L.B. and X.Y. performed surgery. C.L.B. and P.W. performed the ciLepr re-expression study. D.K. conceived and supervised the project.

A video of Saline- and STZ-treated littermates during light cycle (10:00 a.m.-11:00 a.m.), showing that STZ-treated mice display voracious feeding behavior during a time when mice are normally at rest.

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.